Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars
Obviously you have to be very careful in reading it. It contains no trace of understanding in its entirety, but the numbers in the results are fascinating.
How do we sum it up?
If you pay people to over eat 1000kcal per day for three weeks they gain weight and they gain liver fat. The group eating extra butter/coconut oil gain the most liver fat (IHTG is intra hepatic triglyceride). From Figure 1:
Unsaturated fat (22% omega six PUFA) causes less IHTG accumulation than saturated fat, similar to an excess 1000kcal of (mostly) sucrose. So saturated fat is bad for your liver and PUFA or sucrose are less problematic. Shrug.
Aside: Almost no-one gets fat because they deliberately over eat. People get fat accidentally, bit by bit plus the occasional splurge, which they cannot then lose. In this study people did NOT accidentally get fat against their will. They over-ate because they were paid to, whether they were hungry or not. Any resemblance to real life is purely accidental. End of ranty aside.
So anyway, let's get to the interesting bit. Lipolysis. The group measured the rate of glycerol appearance, a perfectly reasonable surrogate for the release of FFAs from adipocytes. Under fasting conditions I think you would agree that saturated fat group increased their rate of lipolysis, just a trend, ns, over the three weeks.
Here are the changes in the rates of glycerol release under an hyperinsulinaemic clamp:
OK. Under an insulin infusion of 0.4mIU/kg/min, plus a bit of glucose, the adipocytes which have been exposed to saturated fats are STILL releasing glycerol (and so FFAs). Eating a mix of olive oil, pesto and pecans for three weeks allows lipolysis to drop like a stone when you infuse insulin, p less than 0.01 between these two groups.
This is pure Protons in action. Saturated fat provides an high input of FADH2 at electron transporting flavoprotein dehydrogenase, so reduces the CoQ couple, so promotes reverse electron transport through complex I which will generate superoxide when the NADH:NAD+ ratio is high, ie under caloric surplus. Superoxide is the signal used for setting up insulin resistance, to stop caloric ingress. Beta oxidation of PUFA skips one FADH2 generation for each double bond present so they are crap at signalling insulin resistance by this mechanism. Even under caloric excess, insulin continues to act and packs more calories in to adipocyes. And it refuses to allow lipolysis. It even very slightly (and ns) reduces fasting lipolysis (in graph B above), when insulin is as low as it's going to get on the SAD (in Finland).
Now for some context.
What do we know about the adipocytes of the subjects at the start of the study?
The BMIs were 30, 31 and 33 in the three groups and of the 38 people involved in the study, 22 had impaired fasting glucose at admission.
So these people already have PUFA induced obesity plus complications. That means that their adipocytes have gravitated to a certain (large) size related to their absolute exposure to insulin combined with a PUFA enhanced insulin sensitivity. This adipocyte size is larger than it would have been had the adipocytes mounted the normal resistance to insulin's action which is provided by saturated fats. As caloric ingress made each adipocyte "full", this "fullness" should have be communicated from the mitochondria (as superoxide) to the adipocyte (as insulin resistance) and eventually the brain as satiety (that signal is VERY interesting, another day perhaps). Under PUFA any distended adipocyte does not feel "full", it behaves as if it is still hungry. Whole body hunger follows on from this. Thanks to the cardiological community and their love of PUFA.
Along come three weeks of palmitic acid (plus a few other nice saturated lipids). Now there is plenty of FADH2, a reduced CoQ couple etc etc and the adipocytes are suddenly able to resist insulin... They suddenly realise that they are grossly distended and there is now no way they are going to accept any more calories (even with insulin infused at 0.4mIU/kg/min). In fact, given this new-found "awareness" of their bloated size, they are going to off load as much lipid as possible, in resistance to insulin's bloating signal. This is why they release glycerol (and associated FFAs) in the face of an hyperinsulinaemic clamp...
Of course lipolysis is fine if you accept the fat from your adipocytes and stop feeling hungry, so stop eating. Developing adipocyte insulin resistance gets fat out of distended adipocytes, saturated fat delivers this.
Of course, if you are pouring FFAs out of your adipocytes but some clown is paying you to eat 1000kcal above your preferred daily intake, you are going to have to do something with those FFAs. Failing to take the chance of a hike to the top of some 1000kcal high hill, the fat will end up in your liver. The more lipolysis, the more fat in your liver. In real life you would simply eat less, we know that supplying small amounts of fat to the liver via the portal vein is a potent suppressor of appetite, at least in rats.
This why I love rodent studies of obesity. You cannot pay a mouse to overeat. Any obese mouse gets to be that way because it is hungry. If you make it hungry using linoleic acid to sequester dietary fat in to its adipocytes then its liver will be fine until adipocyte distension releases enough FFAs to then allow fatty liver to develop.
Sorry if all this sounds like a scratched vinyl record about Protons but people will take this current study as proof that saturated fat is bad for you, which is bollocks of course. Or simply as incomprehensible. One of my biggest problems is that the Protons concept provides a logical explanation for many of the "paradoxes" of different fat types. However it is something of a language of its own and I feel I have no shared vocabulary to explain what is going on with people who do not have the concept... Ah well.
Peter
BTW The sucrose arm is interesting too but that's another story for another day. You noticed the ns-reduced weight gain in the sucrose arm? I digress...
Great to habe you back, Peter! What doew "ns" stand for?
ReplyDeleteHi Eric, life has been busy and now it's the school holidays.........
ReplyDeletens = non significant (statistically, not necessarily biologically!)
Peter
So PUFAs delay metabolic damage in the context of SAD at the cost of increased obesity?
ReplyDeleteAnd this narrative is what they constantly arrive at through these studies, PUFA always end up better in blood work tests since they basically provide another way to protect metabolism (liver,muscles, brain) from caloric overload by pushing excess into adipocytes.
And they always start from this perspective that people cant say NO to carbs and sweets and from that perspective PUFA/MUFA are better I guess?
I am just trying to imagine a framework in which the mainstream nutrition operates to reach these irrational conclusions since there are millions of people who are managing their overweight status and numerous health issues with a low/Vlow carb diet.
As the studies come out the patterns somewhat appear all the time:
To show SAT fat is bad overfeed the subjects, if they are rodents or isolated cell preparation then just do a 25mM glucose in the background.
To show vegan diets are great because no SFA just end the study while the subjects are still loosing weight (so supplementing their metabolism with SFA).
As long as the SFA are at the heart of CVD story they cant be recommended and must end up as a bad guy no matter the story, just devise how to get the study to show that and you are a successful researcher or something.
Hi Slobodan,
ReplyDeleteBasically yes. But I have some issues with the concept of hyper caloric food intake. Essentially ALL food intake is hyper caloric. If a big bloke eats just 1500kcal/day you might suggest that this is an hypo caloric diet. But this is not strictly true. If the meal is absorbed over three hours there will be a period during that absorptive phase when even this low caloric supply is in excess of the body’s immediate needs. During the period when nutrient uptake exceeds nutrient need there should be a period during which cells become replete (i.e. insulin resistant) and calories are diverted to adipocytes. At some point the adipocyte becomes full enough to start to refuse calories too (again, they become insulin resistant). At this point rising nutrient levels in the blood due to continued uptake and refusal to store signals satiety to the brain. The mechanism of this is what interests me at the moment and it’s what is messed up by PUFA. But yes, overall PUFA buy metabolic health at the cost of obesity. Unless, as Tucker points out, you do manage to spike your glucose, generate a ton of uncontrolled superoxide and oxidise your PUFA derived cardiolipins triggering a mitochondrial collapse which may leave too little ATP for apoptosis so we end up with necrosis with its signature blood on the tracks…….
Peter
Thanks for the great analysis (as always)!
ReplyDeleteI had a quick look at the paper, here is the exact composition of the 3 diets (SAT, UNSAT, CARB):
- SAT: 76% from SFAs, 21% from monounsaturated FAs [MUFAs], and 3% from polyunsaturated FAs [PUFAs]
- UNSAT: 57% from MUFAs, 22% from PUFAs, 21% from SFAs
- CARB: 100% simple sugars
And the actual foods:
- SAT: 30 g coconut oil, 40 g butter, and 100 g 40% fat containing blue cheese
- UNSAT: 36 g olive oil, 26 g pesto, 54 g pecan nuts, and 20 g butter
- CARB: group of 2.8 dL orange juice, 4.3 dL sugar-sweetened beverage, and 200 g candy
So it looks that both SAT and UNSAT groups ate similat amounts of MUFAs but coming from different sources (butter & cheese vs olive oils, pesto, pecans and some butter).
What we don't know is what kind of oils with PUFAs were in the pesto.
My questions:
1) What is the role of MUFAs when it comes to the insulin sensitivity of the adipose tissue? Is it neutral (as the % in SAT & UNSAT diets are on par), or perhaps..
2) Could it make a difference if the MUFAs are coming from the plants (olive oil, avocado, macademias, almonds, etc) vs animal sources (butter, bacon)?
3) Does it matter if the PUFAs are O6 or O3? Are O3 any safer for us, again when it comes to the insuline sensitizing effect?
4) Does it matter what the sources of the 06/PUFAs are, seed oils vs nuts?
I've tried reading through the entire protons thread a few times, but these are the practical questions I would love to know the answers to.
Hi Tomasz,
ReplyDeleteI view MUFA as the flip side to saturated fats, neither is good or bad, if they are appropriate for your macros. I think your body will sort out what it needs but it’s worth knowing that stearoyl-CoA desaturase knocking-ins usually produce an obese phenotype and knock-outs produce a lean phenotype. It’s not that simple but what is? Overall there is a message there.
In a mitochondrion there are no plant or animal based foods. There is NADH and FADH2. The ratio matters.
Omega 3 vs omega 6? Omega 3s are more insulin sensitising so more obesogenic (less FADH2). As above, if you can restrict calories, they might be called good. But you can’t, so omega 3 are worse. EPA and DHA are different. They are peroxisome destined so are essentially C8 by the time a mitochondrion sees them. They probably do increase the cytoplasmic NADH levels which may not be good overall.
Oils vs nuts? I eat nuts. I tend towards low PUFA macadamias but cook with ground almonds. I try not to stress about any fine detail too much. Stress is bad for you!
BTW, the pesto will have been made with sunflower oil to get the 22% PUFA in the added calories. There will have been a lot of PUFA in the pre study diets took hence the BMIs...
Peter
That will bee "too" rather than "took" in the last line...
ReplyDeletePeter
And "be" rather than "bee" in the addendum. Duh.
ReplyDeletePeter
Thanks! What I find interesting is that the PUFAs and MUFAs is exactly where my "natural" way of eating (i.e. following the appetite) is failing me: I can easily resist carbs or eat some and stop without any cravings afterwards. But I find it really hard to control overeating nuts once I have some. I've also noticed that when I seasonally eat more veggies with olive and less meat or animal fats, it's hard for me to get satiated..
ReplyDeleteInteresting, Tomasz. I had ice cream "cake" for my birthday last night, and it'll take me days to stop the cravings, and I've been low/near zero carb for almost 5 years.
ReplyDeleteI also don't find MUFAs that filling. For instance, I'll have olive oil "salads" of seafood (no actual green things for the "salad"), with vinegar, and sometimes meat with homemade "Italian" dressing (mainly olive oil, some vinegar, etc.), and they don't seem to be as filling as just eating meat. But I do try to get Omega 3s from fish, at least some time(s) per week. (And I haven't actually calculated the ratios of MUFA/PUFA/SAT fat.)
As for the whole Omega 3/Omega 6 stuff, I try to eat less chicken and pork, but sometimes I like to eat eggs, chicken, pork, etc. I try to avoid most nuts, but sometimes have them. Otherwise,I'd have to eat nothing but grass-fed beef and lamb, which is not only quite expensive and difficult to find, but also boring after a while.
CICOpaths clung to that study like a toddler would to his mother's skirt
ReplyDeleteraphi, as you know I have very ltitle contact with t'internet in general, just a few places I go for a fix of confirmation bias. But I guessed the CICOpaths might like this study. What I find slightly more interesting is what the saturophiles make of it. Without Protons what is a reasonable explanation? There are too many studies along these lines, from the molecular "palmate kills" to the whole organism, as here. Does anyone have a nice explanation which does not involve counting NADHs, FADH2s and including superoxide?
ReplyDeleteAll the best
Peter
Hi Peter,
ReplyDeleteI can concoct an alternative explanation along these lines; that the SFAs require UFAS to make TGs in the adipocytes; that UFA promotes fat storage by its "packing" effect, by allowing TG synthesis.
And for some reason I don't understand (more elongation and desaturation enzymes in liver?) it's a bit easier to park the SFAs there than in adipocytes. But even so this principle needs to act in synch with the action of insulin, and the NADH/FADH2 supplies that. That the SFAs can't be packed easily also means they are prioritised to be burned by adipose, and this supplies the superoxide difference.
Here's what I think is a great insight into the mechanism for harm for PUFAs in liver, from Jenny Heathcote in 2002
ReplyDeleteThese studies have suggested that the presence of fat in patients with hepatitis C is associated with markers of progressive liver disease in that fat was associated with increased stellate cell activation, but the mechanism by which this takes place is uncertain.
*It is possible that this occurs secondary to saturation of beta oxidation pathways within mitochondria which then leads to free fatty acids becoming more available to intracellular microsomes where they undergo lipid peroxidation.*
There are three main products of microsomal lipid peroxidation: malondialdehyde, 4-hydroxynonenal, and hydrogen peroxide. Malondialdehyde has been shown to activate stellate cells to produce fibrin, and may be responsible at least in part for liver fibrosis in patients with non-alcoholic steatohepatitis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1773268/
This fits all models - in alcoholic liver disease, beta-oxidation is impaired by NAD+ depletion and microsomal oxidation is upregulated because MEOS is a PUFA pathway repurposed to dispose of ethanol.
In the current paper, increased fat influx to liver when beta-ox is downregulated by high-carb diet means PUFA, which is not restricted, goes to microsomal disposal. Similar to NAFLD with hyperinsulinaemia downregulating beta-ox in presence of high FFA flux.
In keto diet, beta-oxidation is upregulated and can dispose of 4-HNE and 9-0NE.
Livers from rats fed the ketogenic diet had low HNE (0.8 ± 0.1 nmol/g) and ONE (0.4 ± 0.07 nmol/g), similar to rats fed the standard diet. A possible explanation is that the predominant pathway of HNE catabolism (i.e. beta oxidation) is activated in the liver by the ketogenic diet. This is consistent with a 10 fold decrease in malonyl-CoA in livers from rats fed a ketogenic diet compared to a standard diet.
*The accelerated catabolism of HNE lowers HNE and HNE analog concentrations in livers from rats fed the ketogenic diet.*
On the other hand, rats fed the high fat mix diet had high rates of lipid synthesis and low rates of fatty acid oxidation, resulting in the slowing down of the catabolic disposal of HNE and HNE analogs. Thus, decreased HNE catabolism by a high fat mix diet induces high concentrations of HNE and HNE analogs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289253/
This is consistent with reversal of NAFLD with a keto diet that was 15% LA in the RCT of Browning et al.
So I think we are arriving at a grand unified theory here where we have the pathway whereby LA becomes hepatotoxic and can predict its activation by say, fructose, alcohol, insulin etc, but also explain its "safety catch" setting of CHO or energy restriction.
Awesome article, I have a question from my friend who is a "calories in calories out" lunatic.. She said can you lose weight on a keto diet even if you have a calorie surplus.. She insists that everyone must eat 1000cals to lose weight, and to be fair I'm lost for words on her.. Appreciate something so I can shut the cal in cal out people up... Regards Garry
ReplyDeleteYou are talking semantics here. What is caloric excess? If a young, fit, healthy gymrat eats 5000kcal a day, gains muscle, uncouples respiration and has increased thermogenesis plus increased metabolic need of muscle gain she/he might lose fat so long as the increase in uncoupled respiration and metabolic needs of the new muscle exceed the artificially increased caloric intake. And don’t forget NEAT either. I'm a CICO person. But I doubt anyone can genuinely assess CI or CO so we are back to semantics. I like to think of Dr Hall eating 5000kcal of sawdust per day (large increase of oral CI if not of available calories) while sitting in a metabolic chamber (automatic decrease of CO) while being puzzled as to why he doesn't gain weight beyond the constipation induced by the sawdust. I have a warped imagination. Anyone putting a 1000kcal number as a necessity to lose weight is deeply religious. Arguing with religion is not generally very rewarding.
ReplyDeletePeter
Dear Peter,
ReplyDeletesome time ago you've written [...] that fructose is "associated" with fatty liver and that this association is probably causal. [...] with a link to an overfeeding study with high fructose content. I hope I don't miss a thing, but why can we draw from the fructose study that it is involved causally if it's an overfeeding study.
Maybe a little too much bias against fructose here seen the nice argumentation of the post above?
Merry Christmas
Hi Moritz,
ReplyDeleteYes, you have to modify your ideas as more data come in. I suspect there may be more problems from systemic fructose causing inappropriate lipolysis while insulin is high, but there's still a lot to think about, uric acid included......
Peter